Conventional inactivated vaccine, toxoid, and the like are known to have the following drawbacks:
(1) Lack of Defense Against Infection in Natural Infection Route
The natural infection route of bacterial, virus, and the like is, for example, the mucosal membrane of the nasal cavity, the trachea, the intestinal tract, and the like, whereas the vaccine inoculation route is subcutaneous, intramuscular, and the like, which is different from the route described above. It is desired to achieve defense against infection by an inoculation route fit for the actual conditions of the natural infection, particularly defense against infection at the mucosal membrane from vaccine administration via the mucosal membrane.
(2) Low Mucosal Immunity
In the subject for vaccine inoculation, immunoglobulin G (hereinafter, simply referred to as “IgG” or “IgG antibody”) is mainly produced into the blood, and humoral immunity is induced. However, secretory immunoglobulin A (hereinafter, simply referred to as “IgA” or “IgA antibody”) which takes charge of mucosal immunity, is nearly not produced, and therefore, establishment of mucosal immunity is not expected. Furthermore, necessity and effectiveness of IgA antibody are as follows: IgA antibody plays a very important role in clinical immunity by taking charge of mucosal immunity, i.e., defense against infection at the mucosal membrane which is the entrance to infection onto the respiratory organs such as the nasal cavity and the trachea by spray or air, and infection onto the intestinal tract by oral. Furthermore, IgA antibody has cross immunity, i.e., cross-neutralization activity, and broad spectrum for infection defense as much, and also has defense against infection for variant antigen, whereas IgG antibody has high specificity for antigen, but has narrow spectrum for infection defense, leading to nearly not being effective for infection defense against variant antigen.
(3) Necessity of Additional Vaccination and Added Expense
Since IgG antibody is produced low only by one injection of the first immunization, and certain effects cannot be expected, it is required to increase blood IgG antibody value by additional inoculation, so-called booster inoculation of once or more times, based on the conditions of IgG antibody retention later. Therefore, repeated expense and effort are required, and on top of that, the case is often found where the chance of the booster inoculation is not effective for young children, especially infants two-years old or less, who is likely to depart from the chance of the booster inoculation, though the effects are recognized for the elderly, adults, and school children, who are benefited from the chance.
In other words, conventional inactivated vaccine, toxoid, and the like induces mainly production of blood IgG antibody in the subject for vaccine inoculation, and also brings actions and effects of increasing humoral immunity, being recognized for its efficacy. However, it has low performance of inducing IgA antibody production or mucosal immunity, showing the limit about sufficient function and effects for defense against natural infection. From such circumstances, there have been many trials from various sides so far to resolve the drawbacks of the conventional vaccines. For example, it includes improvement of the vaccine antigen in quality or quantity, experimental production of live vaccine replacing inactivated vaccine, development of new inoculation route, mucosal vaccine, and the like, screening of adjuvant, which elevates humoral immunity and cause maintenance thereof, development of mucosal immunity adjuvant, and the like. However, development of mucosal vaccine which is safe and effective has not been achieved.
Hereinafter, development of mucosal vaccine will be explained.
(1) Increase of the Amount of the Vaccine Antigen
A trial has been conducted of increasing the amount of the vaccine antigen which is inoculated subcutaneously or intramuscularly, or increasing the amount of IgG and IgA antibodies, which are secreted to the mucosal membrane. For example, a method wherein neuraminidase of the virus membrane protein is added to and mixed with conventional inactivated influenza vaccine to increase antibody production amount, or a method wherein MF59 is added and mixed as an adjuvant, and the like has been tried. However, these methods have been found to have disadvantages such as incurrence of pain, strong adverse reaction, and the like.
(2) Vaccine of Nasal Administration Type
A method has been tried wherein liquid split antigen is directly inoculated nasally for infection defense by IgA antibody, which is considered most effective, but the fact is pointed out that IgA production amount is small. In order to elevate IgA antibody production ability, there has been a trial that Escherichia coli heat-labile live toxin or cholera toxin is added to and mixed as an adjuvant with the split antigen to elevate mucosal immunity response, i.e., IgA antibody production ability. However, from the circumstances that the safety of the toxin as an adjuvant has been not proved, the trial treatment has been stopped, and not been put to practical use.
(3) Live Vaccine Using Cold-Attenuated Strain Which Can be Inoculated Into the Nasal Cavity
A method is put to practical use wherein cold-attenuated influenza virus strain, which has optimal growth temperature of 25° C., and does not grow at 39° C., but the risk of toxicity recovery cannot be denied as the mechanism of attenuation of the parent cold-attenuated strain is not clear. In addition, since the active ingredient of the vaccine is a live virus, it has high invasion force into cells and excellent in initialization of immunity, but mild influenza symptoms often incur, so defects have been found that it cannot be used for human who has high risk of increase in severity when infected by influenza, elderly people, and the like.
(4) Other Vaccines
Developments of a vector vaccine which has vaccinia virus as a virus vector, attenuated live vaccine by reverse genetics, DNA vaccine which uses DNA or cDNA as an active ingredient, have been in progress in lab level, but not put to practical use.
Furthermore, development of immunity adjuvant will be explained below.
(1) Immunity Adjuvant
The immunity adjuvant is a general name of a substance which has regulation activity such as reinforcement or inhibition of immune response, and largely divided into two kinds: a substance which is related to a dosage form for the purpose of sustained-release, retention, and the like of antigen within the subject for inoculation, and a substance which helps elevation, inhibition, and the like of immune response. Between them, as the former, i.e., as the adjuvant for dosage form, for example, vaccine or toxoid with use of aluminum phosphate, alum, and the like has been already put to practical use. However, the latter, i.e., the adjuvant which helps reinforcement/elevation of immune response has not been known yet to be put to practical use. For example, BCG live bacteria derived from bacteria, BCG-CWS, endotoxin, glucan, and the like, synthesized MDP, levamisole, Poly I-Poly C, bestatin, and the like, and interferons such as cytokines, TNF, CSF, and the like have been known, but it is considered that guarantee for the safety and efficacy is needed for the practical use of them, by the reasons of insufficient effects, and the like for adjuvant diseases such as arthritis, chronic arthritic rheumatism, hyper-γ-globulinemia, anemia, and the like. In addition, a technique is known (Patent Document 1) using a pulmonary surfactant/protein derived from a higher animal as an adjuvant in order to enhance induction of humoral immunity, but it has not known to be put to practical use.
(2) Development of Adjuvant for Mucosal Immunity
Various adjuvants have been developed, for example, pertussis toxin B oligomer (Patent Document 2), cholera toxin (Patent Document 3), Escherichia coli heat-labile enterotoxin B subunit (LTB) (Patent Document 4), starch particles (Patent Document 5), cholera toxin B chain protein (CTB) (Patent Document 6), B subunit of verotoxin 1 (Patent Document 7), oligonucleotide (Patent Document 8), interleukin 12 (Non-Patent Document 1), and the like. However, they have not been put yet to practical use.
As described above, necessity has been recognized widely and deeply for replacement of the conventional vaccine which is inoculated subcutaneously, intramuscularly, and the like with a mucosal vaccine which induces production of IgA antibody in the mucosal membrane, which is a natural infection route of virus. Particularly, as a vaccine of next generation in the 21 century, so-called mucosal vaccine, which induces production of IgA antibody, and local immunity or mucosal immunity, is expected and hoped worldwide to be developed and put to practical use, but not yet achieved. The reason is considered to be in the fact that safe and effective adjuvant, which imparts the function of inducing production of IgA antibody, and local immunity or mucosal immunity to vaccine, has not specified or established.    Patent Document 1: JP-T-2002-521460    Patent Document 2: JP-A-3-135923    Patent Document 3: JP-T-10-500102    Patent Document 4: JP-T-2001-523729    Patent Document 5: JP-T-2002-50452    Patent Document 6: JP-A-2003-116385    Patent Document 7: JP-A-2003-50452    Patent Document 8: The pamphlet of PCT WO 00/20039    Non-Patent Document 1: pp. 4780-4788, vol. 71, 2003, Infection and Immunity    Non-Patent Document 2: pp. 2-11, vol. 10, 2004, Journal of neonatal Nursing    Non-Patent Document 3: pp. 9-14, vol. 74 (suppl. 1), 1998, Biology of the Neonate    Non-Patent Document 4: pp. 452-458, vol. 24, 2001, American Journal of Respiratory Cell and Molecular Biology